EP2413910A1

EP2413910A1 - Pills comprising dapoxetin and dry processing methods for the production thereof

Info

Publication number: EP2413910A1
Application number: EP10711165A
Authority: EP
Inventors: Frank Muskulus; Jana Pätz
Original assignee: Ratiopharm GmbH
Current assignee: Ratiopharm GmbH
Priority date: 2009-03-31
Filing date: 2010-03-30
Publication date: 2012-02-08
Also published as: WO2010112203A1; DE102009015702A1

Abstract

The invention relates to pills, comprising dapoxetin or a pharmaceutically agreeable salt thereof and pharmaceutical auxiliary agents, particularly adhesion agents, wherein the pills comprise a uniformity of content from 85 % to 115%. The invention further relates to a dry processing method for the production thereof. The pills according to the invention may comprise dapoxetin in crystalline or amorphous form. Thus, the invention furthermore relates to an intermediate, comprising dapoxetin in amorphous form and to a method for the production thereof.

Description

Tablets containing dapoxetine and dry processing for their preparation

The invention relates to tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and pharmaceutical excipients, in particular adhesives, wherein the tablets have a uniformity of the content of preferably 95% to 105% and dry processing process for their preparation. The tablets of the invention may contain dapoxetine in crystalline or amorphous form. Consequently, the invention further relates to an intermediate containing dapoxetine in amorphous form and a process for its preparation.

Dapoxetine belongs broadly to the group of Selective Serotonin Re-uptake Inhibitors (SSRIs), in particular it inhibits the transport molecule of serotonin.

The chemical name of dapoxetine [INN] is (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) -propanamine. The chemical structure of dapoxetine is shown in formula (1) below:

(1) dapoxetine

The synthesis of dapoxetine is described in EP 0 288 188 B1.

EP 1 225 881 B1 relates to the use of dapoxetine for the treatment or management of sexual dysfunction. Capsule and tablet formulations with a dapoxetine content of about 2.5 to 10% by weight are proposed for this purpose. Hard gelatin capsules are often perceived by patients as unpleasant to the oral. With regard to the tablet formulations, however, it has been found during pressing that crystalline dapoxetine (in particular during the transition from an eccentric press to a rotary press) tends to adhere. This leads to undesirable negative qualitative changes of the tablet surface, which complicate a subsequent uniform coating and lead in extreme cases to cover the tablets, especially during prolonged run the Tablettlermaschinen. This leads to undesirable fluctuations in the active ingredient content in the resulting tablets.

It was therefore an object of the present invention to overcome the described disadvantages of the prior art formulations and to provide dosage forms which are pleasant to administer for the patient and ensure reliable drug delivery, in particular with a higher drug content.

In addition, dosage forms of dapoxetine are to be provided which ensure good solubility and bioavailability with simultaneously good storage stability.

Finally, it was an object of the invention to provide a process for the preparation of tablets containing dapoxetine, which show an advantageous paintability. This is important because dapoxetine has a bitter taste and is therefore preferentially coated for taste masking. When coating the tablets of the invention should therefore come to no "chipping".

The tasks could be solved unexpectedly by providing dapoxetine tablets with a high content of content uniformity at medium to high drug content. In particular, it has been found that the objects can be solved particularly advantageously by four preferred inventive aspects, which can be implemented individually or in combination.

In a first aspect of the present invention, the amount of lubricant (compared with the amount of lubricant used in EP 1 225 881 Bl) is increased. In a second aspect, dapoxetine, preferably crystalline dapoxetine, having a specific particle size distribution is used. In a third aspect, the conversion of dapoxetine, especially crystalline dapoxetine, into a stabilized amorphous state occurs. Finally, in a fourth aspect, the processing of dapoxetine into tablets is by dry processing, in particular dry granulation with crystalline dapoxetine or dry granulation or direct compression with stabilized amorphous dapoxetine. The illustrated aspects of the invention represent alternative solutions to the above described objects.

The invention therefore relates to tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and pharmaceutical auxiliaries, in particular adhesives, the tablets having a uniformity of the content of 85% to 115%, determined in accordance with Ph. Eur.6.0, Section 2.9.6, and wherein in particular the active ingredient content is more than 10 to 60 wt .-%. Of the Active ingredient content in the case of coated tablets refers to the total weight of the tablet core. In the case of uncoated tablets, the active ingredient content refers to the total weight of the tablet.

The invention likewise provides a dry granulation process for the production of tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and an adhesion agent comprising the steps

(i) mixing dapoxetine with an adhesive and optionally other pharmaceutical excipients; (ii) compaction into a slug;

(Ui) granulation of the slug; (iv) compression of the resulting granules into tablets, optionally with the addition of further pharmaceutical excipients; and (v) optionally overdrawing, in particular filming the tablets.

The invention further provides an intermediate containing amorphous dapoxetine and an adhesive. The intermediate represents amorphous dapoxetine in stabilized form. The invention further provides various processes for the preparation of stabilized amorphous dapoxetine in the form of the intermediate according to the invention.

The invention relates to tablets containing dapoxetine. In general, the term "tablets" is to be understood as meaning solid pharmaceutical preparations which contain one dose of an active substance (here: dapoxetine) and usually one or more pharmaceutical excipients. Tablets are usually made by pressing a constant volume of substance particles. Tablets are usually for oral use. They are usually either chewed or swallowed preferably chewed, dissolved in water before dissolution or disintegrated or retained for release of the drug in the oral cavity.

The tablets according to the invention (or the tablets produced by the process according to the invention) are preferably tablets which are swallowed whole. In particular, they are coated tablets which are composed of a tablet core and a layer applied thereto.

The tablets according to the invention contain dapoxetine. In the context of this invention, the term "dapoxetine" comprises (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) propanamine according to formula (1) above. In addition, the term "dapoxetine" includes all pharmaceutically acceptable salts as well as hydrates and solvates thereof.

The salts may be acid addition salts. Examples of suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, lactates, butyrates, Propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates. Dapoxetine is preferably used in the context of this invention in the form of the hydrochloride.

The tablets according to the invention have a uniformity of the content of 85% to 115%. (That is, all tablets have an active ingredient content between 85% and 15% of the average active ingredient content.) Preferably, the tablets according to the invention have a uniformity of content of from 90 to 110%, more preferably from 95% to 105%, even more preferably from 96% to 104%, more preferably from 97% to 103% and especially from 98% to 102%. Content Unjformity is determined according to the European Pharmacopoeia (hereafter Ph. Eur.), Issue 6.0, 2008, Section 2.9.6, Examination A. The stated values of the uniformity of the content refer in the context of this invention to a tablet production on a production scale. For this purpose, the dapoxetine content determined by HPLC / UV in 10 randomly sampled from a production batch of 100,000 tablets individually:

The following measuring conditions are to be selected.

As stated above, the tablets according to the invention (or the tablets produced by the method according to the invention) usually have an active ingredient content of more than 10 to 60 wt .-%, preferably from 12 to 55 wt .-%, more preferably from 15 to 50 wt .-%, more preferably from 20 to 45 wt .-%, in particular from 22 to 40 wt .-%, on. The active ingredient content relates, as already explained above, in the case of coated tablets to the total weight of the tablet core. In the case of uncoated tablets, the active ingredient content refers to the total weight of the tablet. In a further preferred embodiment, the tablets according to the invention (or the tablets produced by the process according to the invention) contain 1, 0 to 5.0 wt .-%, more preferably 1, 1 to 4.0 wt .-%, even more preferably 1 , 2 to 3.0 parts by weight, particularly preferably 1, 3 to 2.5 wt .-%, in particular 1, 5 to 2.0 wt .-%, lubricant. The lubricant content refers in the case of coated tablets on the total weight of the tablet core. In the case of uncoated tablets, the lubricant content refers to the total weight of the tablet.

Lubricants are generally agents that lead to a reduction in static friction, sliding friction and / or rolling friction. In particular, lubricants reduce the shear forces occurring at the interface between the tablet and the die. Preferably, lubricants are used in solid form. Preference is given to lubricants which lead to an R value of 0.90 to 0.99, in particular 0.92 to 0.98. The so-called

"R value" is a measure of the effectiveness of the lubricant. The R value is measured on instrumented eccentric presses by comparing the force on the upper punch with the

Force at the bottom of the stamp, see Strickland et al., J. Am. Pharm. Ass., Sei. Ed.

45, 51 (1956). It applies the relationship

R = force at upper punch / force at lower punch.

. Suitable lubricants are for example stearic acid, adipic acid, behenic acid, myristic acid, lauric acid, capric acid, palmitic acid and derivatives thereof, particularly Esterderivate are examples of suitable lubricants are glycerol monostearate, glycerol monopalmitate, sorbitan fatty acid ester (Arlacel ^® - products), Polyethylenoxidfettsäureester (Ethofats ^®), Polyvinylmyristat,

Polyvinyl stearate, diglycol stearate, stearic acid, adipic acid, stearyl alcohol, myristyl alcohol, cetyl alcohol, sodium stearyl fumarate, calcium stearate,

Aluminum stearate, zinc stearate and / or magnesium stearate. Also, polyethylene glycol having a weight average molecular weight of 1000 to 10,000 g / mol, in particular in the form of a particulate composition having a volume average particle size of 0, 1 to 20 microns, more preferably from 1 to 10 μτa than Lubricants are used. Also, talc or defatted milk powder can be used. Finally, inorganic lubricants may be used based on aluminum silicates, for example aluminum hydrosilicates (Gleitol ^®) or bolus alba.

In a further preferred embodiment, the tablets according to the invention are obtainable by compressing dapoxetine in the form of a particulate active ingredient composition having an average particle size (D50) of 0.5 to 150 .mu.m, more preferably from 1 to 80 .mu.m, even more preferably from 2 to 50 .mu.m , particularly preferably from 3 to 35 .mu.m, in particular from 4 to 20 .mu.m, together with pharmaceutical excipients. Analogously, dapoxetine is in the form of the particulate Composition having the above-defined particle size is preferably used in the process according to the invention. The particle sizes given above are based on dapoxetine in crystalline or amorphous form. This was particularly surprising since normally the active ingredient is used in a very fine particle size to improve the solubility, as this increases the wettable surface. However, this is not necessary in the case of dapoxetine because dapoxetine HCl is water soluble according to the USP classification. Furthermore, a too fine active ingredient in a dry processing often leads to segregation, since the added auxiliaries are usually present in a larger particle distribution, so that even a compressibility is ensured and the tablets do not cover. Furthermore, fine active ingredient in very high concentrations (as in the invention) normally leads to poor compressibility up to the capping of the tablets.

The term "mean particle diameter" in the context of this invention always refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry. In particular, for determining a Mastersizer 2000 from Malvern Instruments used (wet measurement, a dispersant is used with ultrasound for 60 seconds, 2,000 rpm, the evaluation according to the Fraunhofer model is carried out, preferably, in which the non-dissolved substance to be measured at 20 ⁰ C ). The average particle diameter, also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, then 50% by volume of the particles have a larger diameter than the D50 value. The terms "average particle size" and "average particle diameter" are used interchangeably throughout this application.

The tablets according to the invention (or the tablets produced by the process according to the invention) preferably have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.01 to 0.2 mm / mg.

Furthermore, the tablets according to the invention (or the tablets produced by the process according to the invention) preferably have a hardness of from 50 to 150 N, particularly preferably from 60 to 120 N, on. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8. The tablets of the present invention have the above-mentioned hardness, in particular, by using the aforementioned preferred amount of lubricant (e.g., 1 to 3% by weight).

In addition, the tablets according to the invention (or the tablets produced by the process according to the invention) preferably show a friability of less than 5%, more preferably less than 3.0%, in particular less than 1.0%. The friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.

In a further preferred embodiment, the tablets according to the invention (or the tablets produced by the process according to the invention) contain dapoxetine in amorphous form. The term "amorphous" is used in the context of this invention as a term for the state of solids in which the building blocks (atoms, ions or molecules, ie in the case of amorphous dapoxetine the dapoxetine molecules) no periodic arrangement over a larger area (= remote order) exhibit. In amorphous materials, the building blocks are usually not completely random and arranged purely statistically, but distributed so that a certain regularity and similarity with the crystalline state in terms of distance and orientation of the nearest neighbors can be seen (= Nahordnung). Consequently, amorphous substances preferably have close proximity but no long-range order.

Solid amorphous materials are isotropic in contrast to the anisotropic crystals. They usually have no defined melting point, but gradually go over slow softening in the liquid state. Their experimental differentiation of crystalline materials can be done by X-ray diffraction, which gives them no sharp, but usually only a few diffuse interferences at small diffraction angles.

In particular, the amorphous dapoxetine is in stabilized form, i. in the form of an intermediate containing amorphous dapoxetine and adhesive. The intermediate according to the invention can generally be used for the formulation of medicaments. It is preferably used in the dry processing method according to the invention, in particular dry granulation method or in a direct compression.

The dry granulation process of the present invention is a process for producing tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and adhesives comprising the steps

(i) mixing dapoxetine (e.g., amorphous dapoxetine in the form of the intermediates of the invention or crystalline dapoxetine) with

Adhesion agents and optionally further pharmaceutical excipients; (U) compaction into a scab; (iii) granulation of the slug;

(iv) compression of the resulting granules into tablets, optionally with the addition of further pharmaceutical excipients; and

(v) optionally overdrawing, in particular filming the tablets. As an alternative to the above-mentioned dry granulation process, the tablet can also be produced by direct compression. Direct compression is particularly preferred when dapoxetine is used in amorphous form or when dapoxetine is given in crystalline form together with the amount of lubricant indicated above as preferred (eg 1 to 3%). The direct compression corresponds to the method described above, omitting the steps (ii) and (Ui).

Thus, the subject of the invention is a process for the preparation of dapoxetine tablets by direct compression, comprising the steps

(i) mixing amorphous dapoxetine in the form of the intermediates according to the invention with adhesion agent and optionally further pharmaceutical auxiliaries;

(iv) compression of the resulting mixture into tablets, optionally with the addition of further pharmaceutical excipients; and

(v) optionally overdrawing, in particular filming the tablets.

The invention likewise provides a process for the preparation of dapoxetine tablets by direct compression, comprising the steps of (i) mixing crystalline dapoxetine with adhesion agent, lubricant and, if appropriate, further pharmaceutical excipients, the amount of lubricant being from 1 to 5% by weight, preferably 1, From 1 to 4.0% by weight, more preferably from 1.2 to 3.0% by weight, particularly preferably from 1.3 to 2.5% by weight, in particular from 1.5 to 2.0% by weight , is; (iv) compression of the resulting mixture into tablets, optionally with the addition of further pharmaceutical excipients; and (v) optionally overdrawing, in particular filming the tablets.

The lubricant content refers in the case of coated tablets on the total weight of the tablet core. In the case of uncoated tablets, the lubricant content refers to the total weight of the tablet.

In step (i) dapoxetine and adhesives, and optionally other pharmaceutical excipients (described below) are mixed. The mixing can be done in conventional mixers. For example, the mixing in positive mixers or gravity mixers can be done, for example by Turbula ^® T 1Ob (Bachofen AG, Switzerland). Alternatively, it is possible that the dapoxetine is first mixed with only a part of the excipients (eg 50 to 95%) before compaction (ii) and that the remaining part of the adjuvants is added after the granulation step (iii). In the case of multiple compaction, the admixing of the excipients should preferably take place before the first compaction step, between several compaction steps or after the last granulation step. The mixing conditions in step (i) and / or the compacting conditions in step (ii) are usually selected to cover at least 30% of the surface area of the resulting dapoxetine particles with adhesive, more preferably at least 60% of the surface, most preferably at least 80 % of the surface, in particular at least 95% of the surface.

In step (U) of the process according to the invention, the mixture from step (i) is compacted into a rag. This is dry compaction, i. the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.

The compaction is preferably carried out in a roll granulator.

The rolling force is usually 3 to 70 kN / cm, preferably 5 to 40 kN / cm, more preferably 10 to 30 kN / cm.

The gap width of the rolling granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, in particular 1.8 to 2.8 mm.

The compacting device used preferably has a cooling device. In particular, it is cooled in such a way that the temperature of the compactate 50 ⁰ C, in particular 40 ⁰ C, does not exceed.

In step (iii) of the process, the slug is granulated. The granulation can be carried out by methods known in the art. For example, the granulation is carried out with the device Comil ^® U5 (Quadro Engineering, USA).

In a preferred embodiment, the granulation conditions are selected such that the resulting particles (granules) have a volume average particle size ((D ₅₀ ) value) of 50 to 800 microns, more preferably 100 to 550 microns, even more preferably 150 to 400 microns , in particular from 200 to 350 microns.

Furthermore, the granulation conditions can be selected so that not more than 55% of the particles have a size of less than 200 microns or the average particle diameter (D50) is between 100 and 450 microns.

Furthermore, the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.2 to 0.85 g / ml, more preferably 0.3 to 0.8 g / ml, especially 0.4 to 0.7 g / ml exhibit. The Hausner factor is usually in the range of 1, 03 to 1, 3, more preferably from 1, 04 to 1, 20 and in particular from 1, 04 to 1, 15. In this case, "Hausner factor" is the ratio of tamped density understood to bulk density. In a preferred embodiment, the granulation is carried out in a sieve mill. In this case, the mesh size of the sieve insert is usually 0.1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, in particular 0.8 to 1, 8 mm.

In a preferred embodiment, the method is adapted such that a multiple compaction takes place, wherein the granulate resulting from step (111) is recycled once or several times for compaction (U). The granules from step (iii) are preferably recycled 1 to 5 times, in particular 2 to 3 times.

The granules resulting from step (iii) can be processed into pharmaceutical dosage forms. For this purpose, the granules are filled, for example, in sachets or stickpacks. The invention therefore also relates to stick packs and sachets containing a granulated pharmaceutical composition obtainable by the dry granulation process according to the invention.

Preferably, the granules resulting from step (iii) are compressed into tablets (= step (iv) of the process according to the invention).

In step (iv), compression into tablets occurs. The compression can be done with tableting machines known in the art. The compression is preferably carried out in the absence of solvents.

Examples of suitable tableting machines are eccentric presses or concentric presses. For example, a fats ^® 102i (Fette GmbH, Germany) are used. In the case of rotary presses, a pressing force of from 1 to 40 kN, preferably from 3 to 25 kN, in particular from 4 to 15 kN, is usually used.

In step (iv) of the process, pharmaceutical excipients may optionally be added to the granules of step (iii). The amounts of excipients added in step (iv) usually depend on the type of tablet to be prepared and on the amount of excipients already added in steps (i) or (ii).

In optional step (v) of the process according to the invention, the tablets from step (iv) are coated, preferably film-coated. In principle, coatings without influence on the drug release, enteric coatings, and delayed-release coatings are possible. Coatings that do not affect drug release are usually water-soluble (preferably have a water solubility greater than 250 mg / ml). Enteric coatings have a pH-dependent solubility. Retarded coatings are usually not water-soluble (preferably they have a water solubility of less than 10 mg / ml at 20 ⁰ C). For the coating (e), preferably for the coating (e), usually macromolecular substances are used, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac or natural gums, such as carrageenan.

Preferred examples of film-forming agents which have no effect on drug release are methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA) and mixtures thereof. The polymers mentioned should usually have a weight-average molecular weight of 10,000 to 150,000 g / mol.

Particularly preferably used is HPMC, in particular HPMC having a weight-average molecular weight of 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH ₃ groups of 1.2 to 2.0.

The layer thickness of the coating (e) is usually 0.5 to 100 μm, in particular 2 to 60 μm. In the case of immediate-release coatings, the layer thickness is preferably from 1 to 5 μm. In the case of slow-release coatings, the layer thickness is preferably 10 to 80 μm, in particular 15 to 60 μm.

In the process according to the invention and the intermediate according to the invention an "adhesive" is used. Likewise, an adhesion agent is preferably used in the tablet according to the invention.

The adhesive is generally a substance capable of stabilizing dapoxetine in compacted or compressed form. The addition of the adhesion agent usually leads to an enlargement of the interparticle surfaces on which bonds can form (for example during the compression process). Furthermore, adhesives are characterized by the fact that they increase the plasticity of the tableting mixture, so that solid tablets are formed during the compression. In addition, suitable adhesives are capable of stabilizing dapoxetine in amorphous form.

In one possible embodiment, the adhesive is a polymer. Furthermore, the term "adhesive" also includes substances that behave polymer similar. Examples are fats and waxes. Furthermore, the adhesive comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides.

The adhesive used in the context of this invention is preferably a polymer having a glass transition temperature (Tg) of greater than 15 ⁰ C, more preferably from 30 ⁰ C to 150 ⁰ C, in particular from 40 ⁰ C to 100 ⁰ C. , The "glass transition temperature" (Tg) is the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state. In this case, a significant change in physical characteristics, z. As the hardness and elasticity, a. Below the Tg, a polymer is usually glassy and hard, above the Tg it turns into a rubbery to viscous state. The determination of the glass transition temperature is carried out in the context of this invention by means of differential scanning calorimetry (DSC). For this purpose, z. B. a device from Mettler Toledo DSC 1 can be used. It is at a heating rate of 1 -20 ° C / min, preferably 5-15 ° C / min or with a cooling rate of 5-25, preferably 10-20 ° C / min, worked.

Further, the polymer usable as the adhesive agent preferably has a weight average or number average molecular weight of from 1,000 to 500,000 g / mol, more preferably from 2,000 to 90,000 g / mol. When the polymer used to prepare the intermediate is dissolved in water in an amount of 2% by weight, the resulting solution preferably exhibits a viscosity of from 0.1 to 8 mPa * s, more preferably from 0.3 to 7 mPa * s , in particular from 0.5 to 4 mPa-s, measured at 25 ⁰ C, and preferably according to Ph. Eur., 6th edition, Chapter 2.2.10 determined.

Preference is given to using hydrophilic polymers for the preparation of the intermediate. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups.

The intermediate according to the invention may comprise, for example, the following polymers as adhesion agents: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC), preferably low-substituted hydroxypropylcellulose (L- HPC); microcrystalline cellulose, guar gum, alginic acid and / or alginates; synthetic polymers such as polyvinylpyrrolidone, polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ^® VA64, BASF), polyalkylene glycols such as polypropylene glycol or, preferably, polyethylene glycol, copolymers block polymers of polyethylene glycol, particularly block co-polymers of polyethylene glycol and polypropylene glycol (Pluronic ^®, BASF), and mixtures of said polymers.

Polyvinylpyrrolidone, preferably having a weight-average molecular weight of from 10,000 to 60,000 g / mol, in particular from 12,000 to 40,000 g / mol, of a copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of, is particularly preferably used as the adhesive 40,000 to 70,000 g / mol and / or polyethylene glycol, in particular having a weight-average molecular weight of 2,000 to 10,000 g / mol, and HPMC, in particular having a weight-average molecular weight of 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of 10 to 35% and a proportion of hydroxy groups from 1 to 35%. Furthermore, it is possible with preference to use microcrystalline cellulose, in particular those having a specific surface area of 0.7-1.4 m ² / g. The specific surface area was determined by gas adsorption method according to Brunauer, Emmet and Teller. The determination of the weight-average molecular weight is preferably carried out by gel permeation chromatography.

Furthermore, the adhesive also includes solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides. Examples of suitable sugar alcohols and / or disaccharides are lactose, mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. The term sugar alcohols here also includes monosaccharides. In particular, lactose and mannitol are used as adhesives.

Furthermore, mixtures of said adhesives are possible.

In preferred embodiments of the present invention dapoxetine and adhesives are used in an amount wherein the weight ratio of dapoxetine to adhesive is 10: 1 to 1:20, more preferably 5: 1 to 1:10, even more preferably 2: 1 to 1: 5 , in particular 1: 1 to 1: 3.

It is advantageous if the adhesive is used in particulate form and the volume-average particle size (D50) of the adhesive is less than 500 μm, preferably 5 to 300 μm, in particular 50 to 250 μm.

Another object of the invention is a method for identifying a pharmaceutical excipient which is suitable as an adhesion agent for amorphous dapoxetine, and thus can be used for the preparation of the intermediate according to the invention. The method comprises the steps:

α) providing a pharmaceutical excipient which is in solid state at 25 ⁰ C. For this purpose, in general, the pharmaceutical auxiliaries mentioned in the European Pharmacopoeia can be selected.

β) Twice successive heating of the solid excipient by means of DSC. Here, two warm-up curves are recorded by DSC. The curves are usually recorded from 20 ⁰ C to a maximum of 20 ⁰ C below the decomposition range of the substance to be tested.

For this purpose, a device of Mettler Toledo DSC 1 can be used. It is at a heating rate of 1 -20 ° C / min, preferably 5-15 ° C / min, or at a cooling rate of 5-25 ° C / min, preferably 10 -20 ° C / min, worked.

γ) Selection of the excipient as "suitable", provided that in the second DSC warm-up curve, a glass transition point of 30 ⁰ C to 150 ⁰ C, preferably from 40 ⁰ C to 100 ⁰ C, can be seen.

The invention also relates to intermediates containing amorphous dapoxetine and a pharmaceutical excipient selected by means of the methods described above.

It is preferred that the type and amount of the adhesive agent be chosen so that the resulting intermediate has a glass transition temperature (Tg) of more than 20 ⁰ C, preferably> 30 ⁰ C.

It is preferred that the type and amount of the polymer be chosen so that the resulting intermediate is storage stable. By "storage-stable" is meant that in the intermediate according to the invention after 3 years storage at 25 ⁰ C and 50% relative humidity, the proportion of crystalline dapoxetine - based on the total amount of dapoxetine - not more than 60% by weight, preferably not more than 30% by weight. %, more preferably at most 15 wt .-%, in particular at most 5 wt .-%, is.

In a preferred embodiment, the intermediates according to the invention additionally comprise, in addition to amorphous dapoxetine and adhesive, a crystallization inhibitor based on an inorganic salt, an organic acid or a polymer having a weight-average molecular weight (Mw) greater than 500,000 g / mol. In the context of this invention, these polymers which are suitable as crystallization inhibitors are also referred to as "highly viscous polymers." Their weight-average molecular weight is usually less than 5,000,000 g / mol A preferred high-viscosity polymer is polyvinylpyrrolidone, preferably having the above-mentioned molecular weight, in particular having a weight-average molecular weight from 600,000 to 900,000 g / mol.

The crystallization inhibitor is preferably ammonium chloride, citric acid or povidone K 90 (according to Ph. Eur. 6.0). The crystallization inhibitor may generally be used in an amount of from 1 to 30% by weight, preferably from 2 to 25% by weight, more preferably from 5 to 20% by weight, based on the total weight of the intermediate.

The intermediates according to the invention can be obtained by various preparation processes. The invention further provides a process for the preparation of the intermediate according to the invention. Hereinafter, five preferred embodiments for such a method will be explained.

In a first preferred embodiment, the invention relates to a freeze-drying method, i. a process for the preparation of the intermediate according to the invention, comprising the steps

(al) dissolving the dapoxetine, preferably the crystalline dapoxetine and the adhesive in a solvent or solvent mixture, and

(bl) freeze-drying the solution from step (a1).

In step (a), dapoxetine, preferably crystalline dapoxetine and the above-described adhesive, dissolved in a solvent or solvent mixture, preferably completely dissolved.

Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preference is given to water, in particular "Aqua purificata" according to Ph.Eur. 6.0 used.

Suitable adhesives in this embodiment are in particular modified celluloses such as HPMC and sugar alcohols such as isomalt, mannitol and sorbitol.

If the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, this may likewise be added in step (a1). With regard to the type and amount of the crystallization inhibitor, reference is made to the above statements.

The solution from step (al) is cooled to about 10 ⁰ C to 50 ° C below the freezing point (ie brought to freezing). Subsequently, the solvent is removed by sublimation. This is preferably done when the conductivity of the solution is less than 2%. The sublimation temperature is preferably determined by the intersection of product temperature and Rx - 10 ⁰ C. Sublimation is preferably at a pressure of less than 0.1 mbar. After sublimation, the lyophilized intermediate is warmed to room temperature.

The process conditions in this first embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D50) of from 1 to 250 μm, more preferably from 2 to 15 μm, in particular from 3 to 30 μm.

In a second preferred embodiment, the invention relates to a "pellet layering process", i. a process for the preparation of the intermediate according to the invention, comprising the steps

(a2) dissolving the dapoxetine, preferably the crystalline dapoxetine and the adhesive in a solvent or solvent mixture, and

(b2) spraying the solution from step (a2) onto a carrier core.

In step (a2), dapoxetine, preferably crystalline dapoxetine and the above-described adhesive, dissolved in a solvent or solvent mixture, preferably completely dissolved.

Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preference is given to water, in particular "Aqua purtficata" according to Ph.Eur. 6.0 used.

Suitable adhesives in this second embodiment are in particular modified celluloses such as HPMC, sugar alcohols such as isomalt and sorbitol and polyethylene glycol, in particular polyethylene glycol having a molecular weight of 2,000 to 10,000 g / mol.

If the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, then this can likewise be added in step (a2). With regard to the type and amount of the crystallization inhibitor, reference is made to the above statements.

In step (b2), the solution from step (a2) is sprayed onto a carrier core. Suitable carrier cores are particles consisting of pharmaceutically acceptable adjuvants, in particular so-called "neutral pellets". To be favoured

Used pellets, which are available under the trade name Cellets ^® and a Mixture of lactose and microcrystalline cellulose contain or Sugarspheres, which represent a mixture of starch and sugar.

Preferably, step (b2) takes place in a fluidized-bed dryer, for example in a Glatt GPCG 3 (Glatt GmbH, Germany). Preference is given to supply air temperatures of 60 ⁰ C to 80 ⁰ C, worked with product temperatures of 30 ⁰ C to 40 ⁰ C and with a spray pressure of 1 to 1, 5 bar.

The process conditions in this second embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D ₅₀ ) of from 50 to 800 /, more preferably from 150 to 650 /, in particular from 250 to 480 /.

In a third preferred embodiment, the invention relates to a spray-drying process for the preparation of the intermediate according to the invention, comprising the steps

(a3) dissolving the dapoxetine, preferably the crystalline dapoxetine and the

Adhesion agent in a solvent or solvent mixture, and

(b3) spray-drying the solution from step (a3).

The third embodiment is particularly preferred among the six production methods described.

In step (a3), dapoxetine, preferably crystalline dapoxetine and the above-described adhesive, dissolved in a solvent or solvent mixture, preferably completely dissolved.

Suitable adhesives in this embodiment are in particular modified celluloses such as HPMC, polyvinylpyrrolidone and copolymers thereof and sugar alcohols such as isomalt and sorbitol or mixtures thereof.

If the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, this can likewise be added in step (a3) become. With regard to the type and amount of the crystallization inhibitor, reference is made to the above statements.

In the subsequent step (b3), the solution from step (a3) is spray-dried. The spray-drying is usually carried out in a spray tower. For example, a Büchi B-191 is suitable (Büchi Labortechnik GmbH, Germany). Preferably, an inlet temperature of 10 ⁰ C to 150 ⁰ C, preferably 120 ⁰ C to 140 ⁰ C is selected. The amount of air is for example 500 to 800 liters / hour and the aspirator preferably runs at 80 to 100%.

The process conditions in this third embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D ₅₀ ) of from 1 to 250 μm, more preferably from 2 to 100 μm, particularly preferably from 3 to 45 μm, in particular from 4 to 20 μm exhibit.

In a fourth preferred embodiment, the invention relates to a melt extrusion process, i. a process for the preparation of the intermediate according to the invention, comprising the steps

(a4) mixing dapoxetins, preferably crystalline dapoxetine and polymeric adhesive, and

(b4) extruding the mixture.

In step (a4) dapoxetine, preferably crystalline dapoxetine with the

Adhesion agent preferably mixed in a mixer. In this embodiment of the method according to the invention, an adhesive in polymeric form is used.

Suitable polymeric adhesives in this fourth embodiment are in particular polyvinylpyrrolidone and vinylpyrrolidone-vinyl acetate copolymers and also polyvinyl alcohols, methacrylates and HPMC.

If the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid or a highly viscous polymer, this can likewise be added in step (a4). With regard to the type and amount of the crystallization inhibitor, reference is made to the above statements.

In step (b4), the mixture is extruded. In this case, conventional melt extruders can be used. For example, a Leistritz Micro 18 is used. The extrusion temperature depends on the type of polymeric adhesive. Usually it is between 40 ⁰ C and 250 ⁰ C, preferably between 80 ⁰ C and 17O ⁰ C.

The cooled melt is usually comminuted by a rasp screen (e.g., Comil U5) and, consequently, subjected to a uniform grain size.

The process conditions in this fourth embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D ₅₀ ) of 150 to 1000 μm, more preferably a D ₅₀ of 200 to 800 μm.

Instead of granulation of the extrudate can also be done a "direct injection". In this case, the method according to the invention comprises the step

(c4) Injection molding of the extrudate into molds for pharmaceutical dosage forms.

Examples are forms for tablets.

In a fifth preferred embodiment, the invention relates to a milling process, i. a process for the preparation of the intermediate according to the invention, comprising the steps

(a5) mixing dapoxetine, preferably crystalline dapoxetine and adhesive, and

(b5) grinding the mixture from step (a5), wherein the milling conditions are preferably selected such that a transition from crystalline to amorphous dapoxetine occurs.

Preferably crystalline dapoxetine and adhesive are mixed in step (a5). The mixture is ground in step (b5). The mixing can be done before or during the milling, i. Steps (a5) and (b5) can be done simultaneously.

If the intermediate to be prepared additionally contains a crystallization inhibitor based on an inorganic salt or an organic acid, it may also be added in step (a5) or (b5). With regard to the type and amount of the crystallization inhibitor, reference is made to the above statements. The milling conditions are preferably chosen such that a transition from crystalline to amorphous dapoxetine occurs.

The grinding is generally carried out in conventional grinding apparatus, preferably in a ball mill, for example in a Retsch ^® PM 100th

The meal is usually 10 minutes to 5 hours, preferably 20 minutes to 3 hours, more preferably 30 minutes to 2 hours.

Suitable adhesives in this fifth embodiment are in particular polyvinylpyrrolidone, modified celluloses such as HPMC, sugar alcohols such as isomalt and sorbitol and polyethylene glycol, in particular polyethylene glycol having a weight-average molecular weight of 2,000 to 10,000 g / mol.

The process conditions in this fifth embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D ₅₀ ) of 0.1 to 250 μm, more preferably 1 to 45 μm, in particular 2 to 20 μm.

As explained above, the tablets according to the invention may contain crystalline or amorphous dapoxetine. Furthermore, the tablets according to the invention preferably contain the quantities of lubricant indicated above. The tablets according to the invention also contain the above-described adhesive. In addition, the tablets of the invention may contain further pharmaceutical excipients.

These are the adjuvants known to the person skilled in the art, in particular those described in the European Pharmacopoeia.

Examples of auxiliaries used are disintegrants, release agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, wetting agents and / or gelling agents.

As disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water. Suitable disintegrants are e.g. organic disintegrants like

Carrageenan, croscarmellose, carboxymethyl starch, soybean starch derivatives and

Crospovidone. Also alkaline disintegrants can be used. By alkaline disintegrating agents are meant disintegrating agents which when dissolved in water produce a pH of more than 7.0. Suitable alkaline disintegrating agents are salts of alkali and alkaline earth metals. Preferred are sodium, potassium, magnesium and calcium. As anions, carbonate, bicarbonate, phosphate, hydrogen phosphate and dihydrogen phosphate are preferred. Examples are sodium hydrogencarbonate, sodium hydrogenphosphate, calcium hydrogencarbonate and the like.

The disintegrating agents used are preferably croscarmellose and crospovidone.

Disintegrants are usually used in an amount of 0.1 to 15% by weight, preferably 1 to 12% by weight, more preferably 5 to 10% by weight, based on the total weight of the formulation (but without coating), used.

The formulation according to the invention optionally contains fillers. Fillers are generally to be understood as meaning substances which serve to form the tablet body in the case of tablets with small amounts of active ingredient (for example less than 70% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.

Examples of preferred fillers are starch, starch derivatives, treated starch, talc, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and / or potassium chloride. Also Prosolv® ^® (Rettenmaier & Söhne, Germany) can be used.

Fillers are usually used in an amount of from 0 to 60% by weight, more preferably from 5 to 40% by weight, based on the total weight of the formulation (but without coating).

An example of an additive to improve the powder flowability (= flow regulator) is dispersed silica, such as known under the trade name Aerosil ^®. Preference is given to using silicon dioxide having a specific surface area of from 50 to 400 m ² / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition of 2.9.26.

Additives for improving the powder flowability are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation.

It is in the nature of pharmaceutical excipients that they partially perform multiple functions in a pharmaceutical formulation. In the context of this invention, the unambiguous delimitation is therefore preferably fiction that a substance which is used as a specific excipient for the production of the tablet core, not at the same time as another pharmaceutical excipient for the production of the tablet core is used. For example, microcrystalline cellulose, if used as in the amount indicated for adhesives, is not additionally used in the amount indicated for disintegrant (although microcrystalline cellulose exhibits some explosive activity).

In the context of this invention, the preferred embodiments explained above can be combined. In a particularly preferred embodiment, the tablet according to the invention contains:

From 12 to 60% by weight, preferably from 20 to 40% by weight, of dapoxetine, in particular dapoxetine

Hydrochloride;

From 20 to 80% by weight, preferably from 25 to 60% by weight, of adhesion agent;

1, 0 to 5.0 wt .-%, preferably 1, 5 to 3 wt .-% lubricant;

0 to 15 wt .-%, preferably 2 to 10 wt .-% disintegrant; and 0 to 3, preferably 0.5 to 2 wt .-% flow control agent.

The above information relates to the weight of the uninfiltrated tablet (= tablet core), but it is preferred that this is coated with a 1 to 50 micron thick film layer. The present invention will be illustrated by the following examples.

EXAMPLES:

Example 1: Preparation of Amorphous Dapoxetine Intermediate by Spray Drying

Process steps:

Dapoxetine hydrochloride was dissolved in water, polyvinylpyrrolidone was added and also dissolved. MCC was suspended in the solution. The solution was spray dried with a ^Büchi® B-191. Aspirator temperature [ ⁰ C] spray diaper

Supply air Air stirring

Time exhaust air quantity

Process step [min] [%] (setpoint) (actual) (actual) [L / h] [% 1 [g / min]

Spraying 95 130 130 80 700 20 6

Example 2: Tabletting of spray-dried dapoxetine

The following composition was processed:

The processing took place by means of the following process steps:

The substances 1-4 were Turbula mixed for 5 min ^® and sieved over 0.5 mm and further mixed for 10 min.

Substance 5 was added to the mixture and mixed for 5 minutes.

The mixture was pressed on an eccentric press (EKO, 9 mm arched).

Core weight: 209.98 mg.

There was no sticking during the tabletting process. The punches were unglued even after prolonged machine running time (100,000 tablets), see Figure 1. The resulting tablets showed advantageous uniformity of content.

Comparative Example 1: Tabletting crystalline active ingredient according to the prior art

The following composition was processed:

Substance 5 was added to the mixture and mixed for 5 minutes. The mixture was pressed on the eccentric press (9 mm arched).

The resulting tablets had an average hardness of 69.8N.

There were significant adhesions in the tabletting process. The punches were already glued after short machine running times (200 tablets), see Figure 2. This led to a covering of the tablets with longer machine running time. The resulting tablets did not show any advantageous uniformity of content.

Example 3: Tableting crystalline active ingredient with increased lubricant content

The following composition was processed:

The substances 1-4 were Turbula mixed for 5 min ^® and sieved over 0.5 mm and further mixed for 10 min. Substance 5 was added to the mixture and mixed for 5 minutes. The mixture was pressed on the eccentric press (9 mm arched).

There was no sticking during the tabletting process. The punches were unglued even after prolonged machine running time (100,000 tablets), see Figure 3. The resulting tablets showed advantageous uniformity of content and advantageous hardness. Despite the increased lubricant content, the tablets had an average hardness of 69.8N. The disintegration time was 1, 0 minutes.

Example 4: Tableting crystalline active ingredient with increased lubricant content and increased proportion of active ingredient

The following composition was processed:

The substances 1-5 were mixed in the Turbula for 5 minutes and sieved over 0.5 mm, and then mixed for a further 10 minutes.

Substance 6 was added to the mixture and mixed for 5 minutes.

The mixture was pressed on the eccentric press (9 mm arched).

There was no sticking during the tabletting process. The stamps were unglued even after a long machine life (100,000 tablets). The resulting tablets showed advantageous uniformity of content. Example 5: Dry Compaction of Crystalline Dapoxetine

The following composition was processed:

Dapoxetine hydrochloride is compacted together with microcrystalline cellulose and L-HPC at a pressure of 15 kN then through a 0.8 mm sieve granulated (Comü ^® U5).

The granulated intermediate is mixed with corn starch, croscarmellose and Aerosil ^® on a Turbula for 10 minutes. Subsequently, magnesium stearate is sieved through a 0.355 μm sieve and the final mixture is mixed again for 2 minutes and then compressed on the eccentric press (arched 9 mm).

The resulting tablets showed advantageous uniformity of content at a high level of active ingredient. The tablets showed advantageous hardness and rapid disintegration time.

Example 6: Direct compression

The following composition was processed:

Ingredients 1-5 were mixed in a blender for 5 minutes at 15 rpm, then the mixture was poured over a 420 μva. Sieve sieved. The sieved mixture was mixed for 10 more minutes at 15 rpm, previously sieved magnesium stearate was added to the above mixture and mixed for 5 minutes at 15 rpm.

The tablet cores were coated with Opadry II 32k575000 gray.

Example 7: Wet granulation

The following composition was processed:

a) dry mix

Ingredients 1-4 were sieved through a 420 μτ sieve and then dry blended for 10 minutes. b) Granulation

The granulation was carried out with aqueous hydroxypropyl cellulose solution and water. The granules were wet-milled in a Comil ^®. The milled granules were dried at 60 ^° C. for 15 minutes. LOD of the dried granules was 1.22% (15 minutes at 105 ^° C.). The dried granules were milled in a Comil ^®. c) lubrication

Previously sieved magnesium stearate was added to the dry milled granules and mixed for 5 minutes at 15 rpm in a mixer.

The tablet cores were coated with Opadry II 32k575000 gray.

Claims

claims

1. Tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and pharmaceutical excipients, wherein the active ingredient content is more than 10.0 to 60 wt .-% and the tablets have a uniformity of the content of 85% to 1 15%, determined according to Ph Eur.6.0, Section 2.9.6.

2. Tablets according to claim 1, which are coated tablets composed of a tablet core and a layer applied thereto.

3. Tablets according to claim 2, containing 1, 0 to 5.0 wt .-% lubricant, based on the total weight of the tablet core, in particular lubricant having an R value of 0.90 to 0.99.

4. Tablets according to one of claims 1 to 3, obtainable by pressing

Dapoxetine in the form of a particulate active ingredient composition with an average particle size of 1 to 35 microns together with pharmaceutical excipients.

5. Tablets according to one of claims 1 to 4, containing dapoxetine in amorphous form.

6. A process for the preparation of tablets containing dapoxetine or a pharmaceutically acceptable salt thereof and an adhesion agent, comprising the steps of (i) mixing dapoxetine with an adhesive and optionally other pharmaceutical excipients;

(ii) compaction into a slug;

(iii) granulation of the slug;

(v) optionally, filming the tablets.

A method according to claim 6 wherein the method comprises only steps (i), (iv) and (v) and wherein in step (i) crystalline dapoxetine with an adhesive and lubricant in an amount of 1.0 to 5.0 Wt .-%, and optionally other pharmaceutical excipients is mixed.

8. The method of claim 6, wherein the compaction (ii) is performed in a roll compactor and the rolling force is 3 to 70 kN / cm, preferably 5 to 50 kN / cm.

9. The method of claim 6 or 8, wherein the granulation conditions in step (Ui) are selected so that no more than 55% of the resulting granules particles have a size of less than 200 microns or the average particle diameter (D50) between 100 and 450th μm, and wherein the bulk density is preferably 0.2-0.85 g / ml.

Intermediate containing amorphous dapoxetine and adhesive, preferred for use in a method according to any one of claims 6, 8 or 9.

11. A process for the preparation of an intermediate according to claim 10 comprising amorphous dapoxetine and adhesive, comprising the steps

(al) dissolving dapoxetine and the adhesive in a solvent or solvent mixture, and (bl) freeze-drying the solution of step (a1).

12. A process for the preparation of an intermediate according to claim 10 comprising amorphous dapoxetine and an adhesive, comprising the steps

(a2) dissolving dapoxetine and the adhesive in a solvent or solvent mixture, and

(b2) spraying the solution from step (a2) onto a carrier core.

13. A process for the preparation of an intermediate according to claim 10 comprising amorphous dapoxetine and an adhesive, comprising the steps of (a3) dissolving dapoxetine and the adhesive in a solvent or solvent mixture, and (b3) spray-drying the solution of step (a3).

14. A process for the preparation of an intermediate according to claim 10 comprising amorphous dapoxetine and adhesive, comprising the steps

(a4) mixing dapoxetine and adhesive, and (b4) extruding the mixture.

15. A process for the preparation of an intermediate according to claim 10 comprising amorphous dapoxetine and adhesive, comprising the steps

(a5) mixing crystalline dapoxetine and adhesive, and (b5) grinding the mixture of step (a5), wherein the milling conditions are preferably selected so that a transition from crystalline to amorphous dapoxetine occurs.